PMID- 28487203 OWN - NLM STAT- MEDLINE DCOM- 20180410 LR - 20240213 IS - 1090-2139 (Electronic) IS - 0889-1591 (Print) IS - 0889-1591 (Linking) VI - 65 DP - 2017 Oct TI - MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders. PG - 161-172 LID - S0889-1591(17)30144-7 [pii] LID - 10.1016/j.bbi.2017.04.024 [doi] AB - HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Xing, Yanyan AU - Xing Y AD - Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong 510632, China; Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Shepherd, Nicole AU - Shepherd N AD - Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Lan, Jie AU - Lan J AD - Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Li, Wei AU - Li W AD - Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Rane, Sushmita AU - Rane S AD - Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Gupta, Samir K AU - Gupta SK AD - Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Zhang, Shanxiang AU - Zhang S AD - Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Dong, Jun AU - Dong J AD - Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong 510632, China; Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong 510632, China. Electronic address: dongjunbox@163.com. FAU - Yu, Qigui AU - Yu Q AD - Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States. Electronic address: andyu@iupui.edu. LA - eng GR - R01 AI117835/AI/NIAID NIH HHS/United States GR - U01 AI069911/AI/NIAID NIH HHS/United States GR - R21 AI104268/AI/NIAID NIH HHS/United States GR - R33 AI104268/AI/NIAID NIH HHS/United States GR - C06 RR015481/RR/NCRR NIH HHS/United States GR - U24 MH100928/MH/NIMH NIH HHS/United States PT - Journal Article DEP - 20170506 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 RN - 0 (TIMP1 protein, human) RN - 0 (TIMP2 protein, human) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 0 (Tissue Inhibitor of Metalloproteinases) RN - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2) RN - EC 3.4.24.- (Matrix Metalloproteinases) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - AIDS Dementia Complex/metabolism/physiopathology MH - Adult MH - Blood-Brain Barrier/metabolism MH - Female MH - HIV-1/pathogenicity/physiology MH - Humans MH - Male MH - Matrix Metalloproteinase 2/blood/cerebrospinal fluid/metabolism MH - Matrix Metalloproteinase 9/blood/classification/metabolism MH - Matrix Metalloproteinases/blood/cerebrospinal fluid/*metabolism MH - Middle Aged MH - Neurocognitive Disorders/blood/*metabolism MH - Tissue Inhibitor of Metalloproteinase-1/blood/cerebrospinal fluid/metabolism MH - Tissue Inhibitor of Metalloproteinase-2/blood/cerebrospinal fluid/metabolism MH - Tissue Inhibitor of Metalloproteinases/blood/cerebrospinal fluid/*metabolism PMC - PMC5793222 MID - NIHMS935763 OTO - NOTNLM OT - BBB OT - HIV-1 OT - HIV-1-associated neurocognitive disorders OT - MMPs OT - Neuropathy OT - TIMPs COIS- Conflicts of interest We declare that we have no conflicts of interest. EDAT- 2017/05/11 06:00 MHDA- 2018/04/11 06:00 PMCR- 2018/02/01 CRDT- 2017/05/11 06:00 PHST- 2017/01/10 00:00 [received] PHST- 2017/04/13 00:00 [revised] PHST- 2017/04/30 00:00 [accepted] PHST- 2017/05/11 06:00 [pubmed] PHST- 2018/04/11 06:00 [medline] PHST- 2017/05/11 06:00 [entrez] PHST- 2018/02/01 00:00 [pmc-release] AID - S0889-1591(17)30144-7 [pii] AID - 10.1016/j.bbi.2017.04.024 [doi] PST - ppublish SO - Brain Behav Immun. 2017 Oct;65:161-172. doi: 10.1016/j.bbi.2017.04.024. Epub 2017 May 6.